Abstract 206: Reduction of Hemoglobin-Oxygen Affinity Results in the Improvement of Exercise Capacity in Mice with Chronic Heart Failure
Backgrounds: Exercise intolerance is a major determinant of quality of life in patients with heart failure (HF). In the present study, we investigated whether a reduction in hemoglobin-oxygen affinity could improve exercise capacity of HF mice. Methods: Four weeks after the left coronary ligation, mice showed cardiac dysfunction and chamber dilatation, which were characteristics of HF. Then, we transplanted bone marrow cells (BMC) isolated from the transgenic mice expressing a lower-affinity hemoglobin variant, Presbyterian, into the lethally irradiated mice with HF. Four weeks after BMC transplantation (BMT), the mice were exercised on a treadmill at 10 m/min for 30 min (n=7/group). Furthermore, we used administration of a synthetic allosteric modifier of hemoglobin, 2-[4-[[3,5-dimethylanilino carbonyl)-methyl]phenoxy]-2-methylpropionic acid to verify exercise capacity on a treadmill at 12.5 m/min for 90 min. Four weeks after LCA ligation, MI mice were injected with the allosteric modifier or vehicle (n=12/group). Results: Echocardiography showed no significant differences in chamber size or cardiac function between WT BMT (WT-BMT) and Presbyterian BMT (Pres-BMT) groups either before or 4 weeks after BMT. The transplantation led to a reduction in Hb-O2 affinity and an increase in O2 supply for skeletal muscle without changes in muscle properties. Pres-BMT mice could run 292.6 ± 4.2 m in 30 min, but WT-BMT mice could only 189.3 ± 37.7 m (p<0.01). The allosteric modifier had no effect on heart rate, blood pressure and echocardiographical parameters. However, after 60 min, the treated mice showed a significantly longer running distance than the control mice (treated, 344.7 ± 19.7 m; control, 267.6 ± 33.9 m for 30 min; p<0.05). Conclusions: Reduction of hemoglobin-oxygen affinity resulted in the improvement of exercise capacity of HF. Thus, hemoglobin constitutes a molecular target for the treatment of patients with HF.